The process of protein phosphorylation represents one course by which intracellular signals are propagated in a cellular response. Within the cell, proteins can be phosphorylated on serine, threonine or tyrosine residues and the extent of phosphorylation is regulated by the opposing action of phosphatases, which remove the phosphate moieties.
PTPR.alpha. (also known as protein tyrosine phosphatase receptor type alpha, LCA-related phosphatase; LRP, HLPR, HPTPA, PTPRA, PTPA, PTP-R alpha, PTPRL2 and RPTPA) is a widely expressed member of the family of receptor-like phosphatases. It was cloned from a human hepatoblastoma cell line (Jirik et al., FEBS Lett., 1990, 273, 239-242) and a brain stem cell line (Kaplan et al., Proc. Natl. Acad. Sci. U.S.A., 1990, 87, 7000-7004) and was mapped to chromosome 20p13, a chromosomal region involved in translocations and deletions in myeloid disorders and neoplasms (Jirik et al., Cytogenet. Cell Genet., 1992, 60, 117-118; Kaplan et al., Proc. Natl. Acad. Sci. U.S.A., 1990, 87, 7000-7004).
Kaplan et al. have presented evidence for the existence of two major PTPR.alpha. RNA transcripts of approximately 4.3 and 6.3 kb (Kaplan et al., Proc. Natl. Acad. Sci. U.S.A., 1990, 87, 7000-7004) whose proteins differ in a stretch of 9 amino acid residues situated in the external juxtamembrane segment (Daum et al., J. Biol. Chem., 1994, 269, 10524-10528). The larger of the two species appears to be more prevalent in fetal tissues, suggesting that the differential expression of the two transcripts is developmentally regulated and/or a result of alternative splicing mechanisms (Kaplan et al., Proc. Natl. Acad. Sci. U.S.A., 1990, 87, 7000-7004). Four additional variants have been subsequently identified.
PTPR.alpha. has been identified as a negative regulator of insulin receptor signaling indicating that it may play a key role in insulin action and in the pathophysiology of non-insulin-dependent diabetes (Moeller et al., J. Biol. Chem., 1995, 270, 23126-23131). However, the importance of PTPR.alpha.'s role in insulin signaling is considered unclear. (Cheng, A., et al., Eur. J. Biochem. (2002) 269:1050-1059).
There is a need in the art for compositions that modulate the activity of PTPR.alpha. and methods for their use as a treatment of prophylactic for diseases and conditions associated with alterations in plasma glucose and in insulin levels as well as insulin action, such as for type 2 diabetes.